There are several conventional methods for preparing D-erythro 1-oxoriboses. For example, U.S. Pat. No. 4,526,988 discloses a process for separating alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)propionate consisting of a 3:1 mixture of 3R-hydroxy enantiomers and 3S-hydroxy enantiomers represented by the following formulae 1 and 2 by column chromatography.

wherein R8 and R9 are each independently C1-C3 alkyl.
The 3R-hydroxy enantiomer of Formula I is reacted with a strong acid to hydrolyze the dioxolane group and proceed the lactonization reaction, to obtain 2,2-difluoro-2-deoxy-D-erythro-1-oxoribose (3) having a erythro structure in which the 3-hydroxyl group is oriented downward, as depicted in Reaction Scheme 1 below.

Column chromatography, used in the aforementioned method, is not suitable for mass-production due to limitations on column sizes and the amounts of materials loaded. In particular, column chromatography requires the use of expensive silica gel as column filler and an excess amount of developing solvent, thus disadvantageously involving high costs.
U.S. Pat. Nos. 4,965,374, 5,223,608 and 5,434,254 disclose a method for separating a desired erythro enantiomer (7) as a precipitate from a mixture of erythro and threo lactones, as depicted in Reaction Scheme 2 below, comprising hydrolyzing 3-benzoyloxypropionate ester (4) (as a 3:1 enantiomeric mixture of 3R- and 3S-enantiomers) with an acid, subjecting the compound to azeotropic distillation with water in order to minimize a reverse reaction toward the precursors to provide a lactone ring (5) as a mixture of erythro and threo lactones, protecting the 5-hydroxyl group with a benzoyl group to provide a 3,5-dibenzoyloxy compound (6), and cooling the compound to a low temperature of −5° C. to 10° C. in dichloromethane to separate a desired erythro enantiomer (7) as a precipitate from the mixture of erythro and threo lactones.

wherein Bz indicates a benzoyl group.
This method is characterized in that the 3-benzoyl oxypropionate ester (4), a mixture of 3R- and 3S-enantiomers, is used for the lactone ring reaction without being separated. In particular, in accordance with the method, 3,5-dibenzyl-1-oxoribose (6) (the mixture of erythro and threo) is dissolved in water and the mixture is cooled to a low temperature, thereby readily selectively separating and obtaining the erythro 3,5-dibenzoyl enantiomer (7). However, this method suffers from several disadvantages including use of highly corrosive, toxic, and expensive trifluoroacetic acid in an excessive amount of 3 equivalents or more for the lactone ring reaction, and being uneconomical due to considerably low overall reaction yield (i.e., about 25%) to obtain the 3,5-dibenzoyl enantiomer (7) from the 3-benzoyl oxypropionate ester (4) as a starting material.
In addition, Korean Patent Application No. 10-2004-0057711 suggests a method for preparing a D-erythro enantiomer (11), as depicted in the following Reaction Scheme 3, comprising introducing a stereochemically large protecting group into the hydroxyl group of the compound (8) to obtain a compound (9), treating the compound (9) with a base to obtain a 3R-enantiomer (10) as an optically pure salt, and subjecting the 3R-enantiomer (10) to lactonization under strong acidic conditions to obtain the target D-erythro enantiomer (11).

wherein R10, R11 and R12 are C1-C3 alkyl, R13 is phenyl or substituted phenyl, and M is NH3, Na or K.
This method suffers from disadvantages in that biphenyl-4-carbonyl chloride, the compound used as the protecting group, is costly, as compared to benzoyl and naphthoyl compounds generally used as protecting groups, and 3R-carboxylic acid ester enantiomers can be separated, but 3S-carboxylic acid ester enantiomers cannot be separated.
As apparent from the foregoing, the conventionally known methods have the following disadvantages. The methods are not suitable for mass-production since 3R-hydroxy enantiomers as precursors are separated by the use of column chromatography or introduction of expensive protecting groups in order to synthesize an erythro 1-oxoribose compound by hydrolyzing the 3R-hydroxyl group enantiomers. Selectively obtaining 3R- and 3S-hydroxy compounds using the methods is difficult. Furthermore, although the lactonization reaction is completed in the form of the mixture of 3R- and 3S-hydroxyl compounds, only the erythro enantiomers are selectively separated from an enantiomeric mixture of erythro and threo 1-oxoribose compounds, thus involving a considerably low yield and low economical efficiency.
The 2′-deoxy-2′,2′-difluorocytidine of Formula I is prepared in accordance with a conventional method, as depicted in the following Reaction Scheme 4. More specifically, the 2′-deoxy-2′,2′-difluorocytidine can be prepared by converting a keto moeity in the lactone of the lactone compound (12) into an alcohol to obtain a lactol compound (13), converting the lactol compound into a ribofuranose intermediate (14), into which a highly reactive leaving group is introduced, due to the difficulty of directly glycosylating the 1-hydroxyl group of the lactol compound with a nucleobase, reacting the activated ribofuranose intermediate with a nucleobase to obtain a nucleoside which is subsequently deprotected.

wherein P and P1 are each independently a hydroxyl protecting group, and L is a leaving group.
P and P1, the hydroxyl protecting groups of the compound (12), are benzoyl groups in almost all conventional methods, other than that disclosed in Korean Patent Application No. 10-2004-0057711. Korean Patent Application No. 10-2004-0057711 also has a limitation of restricting the 3-protecting group to 4-phenyl-benzoyl.
It is known that sulfonyloxy and halo groups may be used as the leaving groups, and in particular, the most preferred of the sulfonyloxy groups is α-methanesulfonyloxy ribofuranose.
The glycosylation of Reaction Scheme 5 is carried out in accordance with an SN2 reaction mechanism in which a nucleobase attacks the leaving group on the 1-carbon of D-erythro-ribofuranose and then undergoes substitution. To prepare nucleoside, in which the cytosine base of gemcitabine is oriented in the β-position, in high yield, it is important to obtain an α-anomer having a leaving group in the α-position in high yield.
Generally, in connection with the reaction, in which the nucleobase attacks the leaving group on the 1-carbon of D-erythro-ribofuranose and is then substituted, the leaving group released after the reaction attacks the C-1 position, while competing with the nucleobase, to induce anomerization at the C-1 position, thus shifting a ratio of α-anomers to β-anomers from the initial stage of the reaction. That is, although only α-anomers are used for glycosylation, β-anomers increase in amount with the passage of time. As a result, the reaction proceeds non-steroselectively, thus resulting in production of α-nucleosides as impurities as well as desired β-nucleosides oriented at the β-position.
In the case where the leaving group is sulfonyloxy, such anomerization is decreased. Accordingly, when pure α-sulfonyloxy anomers, for example, α-methanesulfonyloxy compounds, are used, an excess of the desired β-nucleosides can be obtained.
On the other hand, in the case where the leaving group is haloRPS, although only pure α-halo anomers are used for glycosylation, the level of anomerization by halides released after the reaction is relatively high, and β-halo anomers are thus gradually increased as the reaction proceeds. In particular, the β-halo anomers have a higher glycosylation rate than that of α-halo anomers, and the halo leaving group has a lower reactivity than that of the sulfonyloxy leaving group, thus requiring longer reaction time and higher reaction temperature, and therefore showing lower stereoselectivity, allowing the α-nucleosides to increase as the reaction proceeds.
Accordingly, in the preparation of 2′-deoxy-2′,2′-difluoro nucleoside employing the glycosylation reaction, the method using 1-halo-ribofuranose inevitably entails limited stereoselectivity. For this reason, the method for preparing the nucleosides using the α-methanesulfonyloxy ribofuranose is known to be the most excellent of conventionally developed glycosylation methods.
A more-detailed illustration of this method will be given. First, the methods for glycosylating α-sulfonyloxy ribofuranose with nucleobases are disclosed in U.S. Pat. Nos. 5,371,210, 5,401,838, 5,426,183, 5,594,124, and 5,606,048 and European Patent No. 577,303. As depicted in Reaction Scheme 5 below, these methods involve stereoselective glycosylation comprising reacting a 1-sulfonyloxy ribofuranose derivative (15) containing a sufficient amount of anomer with a nucleobase to produce a β-nucleoside (16) in a high ratio.

wherein P and P1 are hydroxyl protecting groups, W is an amino protecting group or hydrogen, L is a leaving group, including sulfonyloxy substituted with nitrile, halo, carboalkoxy or nitro, substituted sulfonyloxy, or substituted arylsulfonyloxy.
In accordance with this method, about 5 to 7-times as many β-nucleosides (16), in which nucleobases are mostly oriented in the β-position, are obtained as α-nucleosides (17) due to good reactivity and a low level of anomerization of the 1-sulfonyloxy leaving group. As a result, gemcitabine can be obtained in yields as high as 30 to 75%.
Meanwhile, U.S. Pat. Nos. 4,526,988 and 5,453,499 and Korean Patent Application No. 10-2005-0041278 disclose 1-α-halo-ribofuranose derivatives into which halo leaving groups are introduced.

wherein P and P1 are hydroxyl protecting groups, Ac is an acetyl group, and X is bromo or chloro.
U.S. Pat. No. 4,526,988 discloses a method for preparing a 1-halo anomer (19), as depicted in Reaction Scheme 6, comprising reacting the 1-hydroxyl group of a lactol compound (13) with acetic anhydride or another acetyl-based source in the presence of 1 equivalent or more of an acid scavenger to prepare a 1-acetate derivative (18) and adding a hydrobromide or hydrochloride gas to the reaction mixture at a low temperature of about −50 to 0° C. to obtain a 1-halo anomer (19). However, this method has a disadvantage of yielding the α-halo anomer in low yield due to low stereoselectivity.

wherein P and P1 are hydroxyl protecting groups such as benzoyl, P2 is sulfonyl and X is halide.
U.S. Pat. No. 5,453,499 discloses a method for preparing a high ratio of α-halo anomers (21) to β-halo anomers of 9:1 to 10:1 by reacting a β-sulfonyloxy compound (20) with a halide source in an inactive solvent, as depicted in Reaction Scheme 7.
The β-sulfonyloxy compound (20) as a starting material is prepared from the corresponding 1-hydroxyl compound disclosed in U.S. Pat. No. 5,401,861. In the preparation of the β-sulfonyloxy compound (20), α-sulfonyloxy anomers and β-sulfonyloxy anomers are prepared in a ratio of 1:4. However, when taking into consideration the process of separating the β-sulfonyloxy anomers from the mixture of α- and β-anomers, although α-halo anomers are obtained in a high ratio of 9:1 to 10:1 (α-anomer:β-anomer) in Reaction Scheme 7 above, a stereoselectivity ratio of the final α-halo anomers (21) to β-halo anomers obtained from the 1-hydroxy compound is at most 3:1. In addition, since the α-halo anomers (21), into which benzoyl groups as 3- and 5-hydroxyl protecting groups are introduced, are yielded in an oil phase, they disadvantageously require the use of column chromatography which is unsuitable for mass-production due to low separation efficiency and low economical efficiency. In particular, the oil phase thus obtained is generally difficult to handle or store, similar to solids.

As depicted in Reaction Scheme 8. Korean Patent Application No. 10-2005-0041278 discloses a method for preparing α-halo anomers (21), comprising reacting a lactol compound (13) with a phosphenyl halide compound in the presence of a base to prepare a 1-phosphenyloxy furanose derivative (22), reacting the compound (22) with a halide source and recrystallizing the resulting product.
However, this method suffers from disadvantages of complicated reaction procedure, and the difficulty of yielding the compound with a high purity due to the difficulty of removing phosphenyl acid obtained as by-products.
In addition, there are several conventional glycosylation methods using 1-haloribofuranose. For example, U.S. Pat. No. 5,744,597 and European Patent No. 577,304 disclose a stereoselective anion glycosylation process, as depicted in Reaction Scheme 9 below, comprising reacting an α-halo anomer-rich ribofuranose derivative (15) with an anionic nucleobase to prepare a β-nucleoside (16) having the nucleobase introduced at the β-position.

wherein P and P1 are hydroxyl protecting groups, W is an amino protecting group, M+ is an anion, and L is iodine or sulfonyloxy.
In accordance with this method, the nucleobase is reacted with a strong base such as potassium t-butoxide or sodium hydride to prepare an anionic nucleobase, and the anionic nucleobase is glycosylated with an α-halo anomer-rich ribofuranose derivative (15) to obtain an α-nucleoside (17) as well as a β-nucleoside (16). This method has several disadvantages of the necessity of an additional troublesome process to prepare the anionic nucleobase, in particular, of yielding an equivalent amount of the desired β-nucleosides and α-nucleosides due to nonstereoselective glycosylation, as mentioned above, and inefficiency and low economical efficiency due to a considerably low separation yield.
As such, in the case where 1-haloribofuranose containing halide as the leaving group is used for glycosylation, although pure α-anomers oriented at the α-position only are used, the glycosylation reaction proceeds nonstereoselectively, unlike the case where α-sulfonate leaving groups are used, thus showing inferior results, namely that the desired α-nucleoside is yielded in a considerably low yield.
In addition, obtaining different P and P1 hydroxyl protecting groups introduced at the 3- and 5-positions, shown in Reaction Scheme 9 above, is difficult, necessitating that P and P1 be identical.